Platelets, also referred to as thrombocytes, are anuclear cell fragments that exist in mammalian blood and mediate blood clot formation and hemostasis. In addition, platelets release growth factors that play a significant role in the repair and regeneration of connective tissues and facilitate wound healing. Platelets are the terminal differentiation product of megakaryocytes (MK), which in turn originate from pluripotent stem cells of the bone marrow. Platelets have an average lifespan of about 5 to 10 days, and their physiological blood level in humans is normally 150,000 to 450,000/uL. When a patient's levels of circulating platelets are depleted below the physiological range, this condition is known as thrombocytopenia.
Thrombocytopenia is typically associated with defective formation of hemostatic plugs and bleeding, wherein the risk of bleeding is inversely proportional to the platelet count. Early diagnosis and treatment are important to prevent progression to more serious symptoms, such as cerebral bleeding.
Four factors (1) failed platelet production, (2) abnormal platelet distribution, (3) increased platelet destruction, and (4) increased platelet consumption are known as the mechanism of thrombocytopenia; however, its pathological features and causes vary widely. Decreased platelet counts can be due to decreased production caused by a number of disease processes including, vitamin B12 or folic acid deficiency, leukemia or myelodysplastic syndrome, decreased production of thrombopoietin by the liver in liver failure, sepsis, systemic viral or bacterial infection, Dengue fever (by direct infection of bone marrow megakaryocytes as well as immunological shortened platelet survival). Decreased platelet counts can be due to a hereditary syndrome, including for example, congenital amegakaryocytic thrombocytopenia (CAMT), Thrombocytopenia absent radius syndrome, Fanconi anemia, Bernard-Soulier syndrome, May-Hegglin anomaly, Grey platelet syndrome, Alport syndrome and Wiskott-Aldrich syndrome. In addition decreased platelet counts can be due to increased destruction of platelets as seen with idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), disseminated intravascular coagulation (DIC), paroxysmal nocturnal hemoglobinuria (PNH), antiphospholipid syndrome, systemic lupus erythematosus (SLE), post-transfusion purpura, neonatal alloimmune thrombocytopenia (NAITP), splenic sequestration of platelets due to hypersplenism and HIV-associated thrombocytopenia. Medications can also produce thrombocytopenia as a negative side effect, including for example the administration of valproic acid, methotrexate, carboplatin, interferon, isotretinoin, panobinostat, and other chemotherapy drugs, Singulair (montelukast sodium) and H2 blockers and proton-pump inhibitors.
In particular, intravenous administration of interferon (IFN) has long been recognized as a therapeutic agent that helps reduce viremia in chronic hepatitis C. Employed widely, it is known that the number of platelets gradually decreases with time after IFNs administration in most patients. IFN must be thus decreased in dose or discontinued in some patients even when continuation of the therapy is desired. The decrease in platelet count is therefore a clinically significant problem. When IFN is administered to patients with hepatic cirrhosis, close attention must be paid, since these patients often exhibit a low platelet count of ≦100,000/uL even before the start of administration. No effective therapeutic method has been established for the adverse drug reaction to IFN.
“Interferon” is a term generically describing a distinct group of cytokines exhibiting pleiotropic activity generally categorized as antiviral, antiproliferative and immunomodulatory. In the early years of IFN research, an international committee was assembled to devise a system for orderly nomenclature of IFNs and defined “interferon” as follows: “To qualify as an interferon a factor must be a protein which exerts virus non-specific, antiviral activity at least in homologous cells through cellular metabolic process involving synthesis of both RNA and protein.” Journal of Interferon Research, 1, pp. vi (1980). “Interferon” as used herein in describing the present invention shall be deemed to have that definition and shall contemplate such proteins and glycoproteins, including for example, the subtypes IFN-α, IFN-β, IFN-δ, IFN-γ, IFN-ε, IFN-κ, IFN-λ, IFN-ω and IFN-tau, regardless of their source or method of preparation or isolation.
Originally identified for their ability to induce cellular resistance to viral infection, IFNs are currently known to be potent mediators in the host defense mechanism and homeostasis, modulating both the innate and adaptive immune responses. IFNs are small, inducible 20-25 K, usually glycosylated proteins that are produced by vertebrate cells in response to various biological stimuli. Mechanistically, IFNs mediate their biological activities by binding to receptors present on the surface of target cells. Specific ligand-receptor interactions trigger intracellular signaling cascade downstream, resulting in the synthesis of proteins that mediate mentioned pleiotropic activities.
IFNs are classified into three groups: type I, type II or type III, based on their structure, physicochemical properties and biological activities. In mammals, eight families of type I IFN have been described. These are: IFN-α, IFN-β, IFN-δ, IFN-ε, IFN-κ, IFN-ω and IFN-tau (IFN-τ). Among these families, trophoblast IFN-τ, found only in ruminant ungulates, is not inducible by virus and is produced in the embryonic trophoectoderm at a specific time, early during pregnancy. Its major function is to create conditions for the completion of pregnancy. IFN-δ (delta), a polypeptide of about 149 amino acids, has been described only in pigs; this IFN is physiologically expressed by trophoblasts during the period of implantation in uterus.
IFN-γ is the sole representative of type II IFN in mammals, while IFN-λ is the sole representative of type III IFN in mammals.
Type I, type II and type III IFNs exert their biological effects through different cellular receptors.
As described herein a method for treating or preventing thrombocytopenia in a subject in need thereof, comprising administering to the subject an oral low dose of IFN so as to elevate the levels of platelets in said subject, thereby treating or preventing thrombocytopenia in said subject. More particularly, the method comprises administering IFN for contact with the mucosal membranes of the digestive and respiratory tract.